EP2822548A1 - Long chain base sphingosine kinase inhibitors - Google Patents
Long chain base sphingosine kinase inhibitorsInfo
- Publication number
- EP2822548A1 EP2822548A1 EP13820704.8A EP13820704A EP2822548A1 EP 2822548 A1 EP2822548 A1 EP 2822548A1 EP 13820704 A EP13820704 A EP 13820704A EP 2822548 A1 EP2822548 A1 EP 2822548A1
- Authority
- EP
- European Patent Office
- Prior art keywords
- mmol
- alkyl
- nmr
- mhz
- compound
- Prior art date
- Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
- Granted
Links
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Classifications
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- C07D413/00—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms
- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/04—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings directly linked by a ring-member-to-ring-member bond
-
- A—HUMAN NECESSITIES
- A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
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- C07D413/02—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings
- C07D413/06—Heterocyclic compounds containing two or more hetero rings, at least one ring having nitrogen and oxygen atoms as the only ring hetero atoms containing two hetero rings linked by a carbon chain containing only aliphatic carbon atoms
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- C07C251/04—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C251/10—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton
- C07C251/12—Compounds containing nitrogen atoms doubly-bound to a carbon skeleton containing imino groups having carbon atoms of imino groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of an unsaturated carbon skeleton being acyclic
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- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/14—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to acyclic carbon atoms
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- C07C257/00—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines
- C07C257/10—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines
- C07C257/16—Compounds containing carboxyl groups, the doubly-bound oxygen atom of a carboxyl group being replaced by a doubly-bound nitrogen atom, this nitrogen atom not being further bound to an oxygen atom, e.g. imino-ethers, amidines with replacement of the other oxygen atom of the carboxyl group by nitrogen atoms, e.g. amidines having carbon atoms of amidino groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C07C2601/14—The ring being saturated
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- C07C271/06—Esters of carbamic acids
- C07C271/08—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms
- C07C271/10—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms
- C07C271/20—Esters of carbamic acids having oxygen atoms of carbamate groups bound to acyclic carbon atoms with the nitrogen atoms of the carbamate groups bound to hydrogen atoms or to acyclic carbon atoms to carbon atoms of hydrocarbon radicals substituted by nitrogen atoms not being part of nitro or nitroso groups
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- C07C279/16—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of rings other than six-membered aromatic rings
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- C07C279/18—Derivatives of guanidine, i.e. compounds containing the group, the singly-bound nitrogen atoms not being part of nitro or nitroso groups having nitrogen atoms of guanidine groups bound to carbon atoms of six-membered aromatic rings
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- C07D249/02—Heterocyclic compounds containing five-membered rings having three nitrogen atoms as the only ring hetero atoms not condensed with other rings
- C07D249/08—1,2,4-Triazoles; Hydrogenated 1,2,4-triazoles
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- C07D263/02—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings
- C07D263/30—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members
- C07D263/32—Heterocyclic compounds containing 1,3-oxazole or hydrogenated 1,3-oxazole rings not condensed with other rings having two or three double bonds between ring members or between ring members and non-ring members with only hydrogen atoms, hydrocarbon or substituted hydrocarbon radicals, directly attached to ring carbon atoms
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/06—1,2,4-Oxadiazoles; Hydrogenated 1,2,4-oxadiazoles
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- C07D271/02—Heterocyclic compounds containing five-membered rings having two nitrogen atoms and one oxygen atom as the only ring hetero atoms not condensed with other rings
- C07D271/10—1,3,4-Oxadiazoles; Hydrogenated 1,3,4-oxadiazoles
Definitions
- the invention relates to inhibitors of Sphingosine Kinase enzymatic activity, and methods of treating diseases and disorders by administering inhibitors of Sphingosine Kinase enzymatic activity.
- Sphingosine 1-phosphate is a lysophospholipid mediator that evokes a variety of cellular processes, including those that result in cell proliferation, cell morphology, tumor-cell invasion, endothelial cell chemotaxis, and angiogenesis. SIP mediates its effects on cellular behavior through the SIP receptors, a family of five cell surface G protein coupled receptors called S1P(1), S1P(2), S1P(3), S1P(4), and S1P(5), which were formerly known as EDG-1, -3, -5, -6, and -8, respectively. In addition to the SIP receptors, SIP also activates various less well-defined intracellular targets.
- the EDG receptors are G-protein coupled receptors (GPCRs) and on stimulation propagate second messenger signals via activation of heterotrimeric G-protein alpha (G a ) subunits and beta-gamma (G Py ) dimers.
- GPCRs G-protein coupled receptors
- G Py beta-gamma
- SIP is synthesized by the action of two enzymes, sphingosine kinase types 1 and 2 (SphKl, SphK2). These enzymes catalyze the transfer of a phosphate residue from adenosine triphosphate (ATP) to D-erythro sphingosine.
- SphKl and SphK2 also catalyze the phosphorylation of reduced sphingosine (D-erythro sphinganine) and hydroxylated sphinganine (D-ribo phytosphingosine) to yield sphinganine 1- phosphate (dihydroSIP) and phytosphingosine 1-phosphate.
- Non-SIP agonist is the phosphorylated form of the immunomodulator, fingolimod (2-amino-2-[2-(4-octylphenyl) ethyl] propane 1,3-diol), which is an agonist of four of the five SIP receptors.
- fingolimod (2-amino-2-[2-(4-octylphenyl) ethyl] propane 1,3-diol
- Enhancing SIP tone at S1P(1) influences lymphocyte trafficking by decreasing lymphocyte egress from secondary lymphoid tissues.
- S1P(1) agonists Consistent with the role of S1P(1) agonists in preventing lymphocyte egress from the vasculature, antagonists of some S1P(1) receptors cause leakage of the lung capillary endothelium, which suggests that SIP may be involved in maintaining the integrity of the endothelial barrier in some tissue beds.
- infection and tissue injury induce a cascade of biochemical changes that trigger reactions of the immune system, collectively referred to as an inflammatory response.
- the evolution of this response is based, at least in part, on enhancing vascular permeability and activation of the vascular endothelium, which allows white blood cells to efficiently circulate and migrate to the damaged site, thereby increasing their chances to bind to and destroy any antigens.
- the vascular endothelium is then thought to be activated or inflamed.
- inflammation is a welcomed immune response to a variety of unexpected stimuli, and as such it exhibits rapid onset and short duration (acute
- chronic inflammation Its persistent or uncontrolled activity (chronic inflammation) has, however, detrimental effects to the body and results in the pathogenesis of several immune diseases, such as: septic shock, rheumatoid arthritis, inflammatory bowel diseases, acute lung injury, pulmonary fibrosis, and congestive heart failure, for example.
- immune diseases such as: septic shock, rheumatoid arthritis, inflammatory bowel diseases, acute lung injury, pulmonary fibrosis, and congestive heart failure, for example.
- chronic inflammation resulting from persistent tissue injury can lead to organ fibrosis, and eventually, organ failure, as is the case in idiopathic pulmonary fibrosis, end- stage renal failure, and liver cirrhosis, for example.
- thrombin thrombin receptors
- PA s thrombin receptors
- Thrombin and thrombin receptors regulate various endothelial functions and play a role in the response of endothelial cells to vascular injury, including inducing cytoskeletal changes resulting in cell rounding. Contraction of endothelial cells leads to increased permeability and compromises in the endothelial barrier. In contrast to the edemagenic effects of thrombin, SIP may enhance endothelial cell barrier properties.
- SIP has also been shown to have a direct role in modulating several important effects on cells that mediate immune functions. Platelets, monocytes and mast cells secrete SIP upon activation, promoting inflammatory cascades at the site of tissue damage. Activation of SphK is required for the signaling responses since the ability of TNF-a to induce adhesion molecule expression via activation of
- Nuclear Factor Kappa B (N FKB) is mimicked by SIP and is blocked by DMS. Similarly, SIP mimics the ability of TNF-a to induce the expression of Cyclooxygenase-2 (COX-2) and the synthesis of
- PGE 2 prostaglandin E 2
- RNA interference blocks these responses to TNF-a.
- SIP is also a mediator of calcium influx during neutrophil activation by TNF-a and other stimuli, leading to the production of superoxide and other toxic radicals. Therefore, reducing the production of SIP within immune cells and their target tissues may be an effective method to treat disorders arising from oxidative stress and abnormal inflammation. Examples of such disorders include inflammatory bowel disease, arthritis, atherosclerosis, asthma, allergy, inflammatory kidney disease, circulatory shock, ischemia-reperfusion injury, post-surgical organ failure, organ transplantation, multiple sclerosis, chronic obstructive pulmonary disease, skin inflammation, periodontal disease, psoriasis and T cell-mediated diseases of immunity.
- SIP also has several effects on cells that mediate immune functions. For example, platelets, monocytes, and mast cells secrete SIP upon activation, promoting inflammatory cascades. It is believed that SphK activation is required for the related signaling responses. In addition, deregulation of apoptosis in phagocytes can be an important component of chronic inflammatory diseases. SIP has been found to protect neutrophils and macrophages in response to inflammatory stresses, such as TNF-a. Additional information regarding the role of SIP and SphK in various specific inflammatory and/or autoimmune conditions can be found in U.S. Patent Application Publication No. 2008/0167352, the disclosure of which is incorporated herein. Accordingly, inhibition of the enzymatic activity of SphK (which can reduce levels of SIP) can prevent the hyperproliferation of immune cells that are important for inflammation.
- SIP also has effects on vascular contractility, vascular tone, and blood pressure control.
- the non-SIP agonist, fingolimod produces modest hypertension in patients (2-3 mmHg in 1-yr trial).
- exogenous SIP elicits a marked Ca 2+ - and ho kinase- dependent pulmonary vasoconstriction in hypertensive rat lungs.
- SIP selectively and potently constricts isolated cerebral arteries. Therefore, reducing SIP levels may be an effective method to treat disease or disorders arising from hypertension. Examples of such diseases or disorders include chronic kidney disease, pulmonary hypertension, pulmonary arterial hypertension, atherosclerosis, and stroke.
- sphingosine kinases are good targets for therapeutic applications such as modulating fibrosis, tumor growth inhibition, angiogenesis, endothelial cell chemotaxis, and inflammatory and autoimmune diseases and disorders.
- SphKl and SphK2 have roles in affecting cell survival and proliferation.
- These kinases are also responsible for the equilibrium between the anti-apoptotic SIP and its pro-apoptotic metabolic precursor sphingosine and its precursor, ceramide.
- SphKl and SphK2 are important drug targets.
- the present invention satisfies these needs.
- the present invention provides, in one aspect, compounds that inhibit sphingosine kinase 1 and sphingosine kinase 2 (SphKl & SphK2) enzymes. Accordingly, there are provided compounds of Formula
- R 2 and R 3 are each independently selected from hydrogen and R d ;
- R d is independently selected from -0(R 18 ), -C(0)R 19 , and -C(O)R 20 -O-C(O)-R 21 ; wherein R 18 is independently selected from hydrogen, (Ci-C 6 )alkyl, (C 6 -Ci 0 )aryl, and (C 6 -Ci 0 )alkylaryl; wherein R 19 is independently selected from (C C 6 )alkyl, (Ci-C 6 )alkoxy, (C C 6 )alkoxyalkyl, (C 6 -Ci 0 )alkoxyaryl, (C 6 -Ci 0 )a and (C 6 -Cio)alkylaryl; wherein R 20 is independently selected from (Ci-C 6 )alkyl; a nd wherein R 21 is independently selected from (C C 6 )alkyl, (C 6 -Ci 0 )aryl, and (C 6 -C 10 )alkyla
- R 4 and R 5 are each independently selected from hydrogen, NH 2 , OH, and (Ci-C 4 )alkyl, or R 4 and R 5 , together with the atom to which they are attached form a saturated or unsaturated 3- to 8- membered ring, wherein said 3- to 8-membered ring is optionally substituted with at least one heteroatom, wherein the at least one heteroatom is independently selected from O, S, N, and NR 7 , wherein R 7 is hydrogen or (Ci-C 3 )alkyl, and wherein said 3- to 8-membered ring is optionally substituted by at least one substituent independently selected from OH, N(R e R f ), halo, (Ci-C 6 )alkyl, (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alkoxy, and (C Ci 0 )alkoxyalkyl; and R 6 is hydrogen
- W is present or absent, but when present, is -C(R 8 R 9 )-, -N(R 10 )-, or -C(O)-;
- V is -C(R 4 R 5 )- and W is -C(R 8 R 9 )- or -N(R 10 )-, R 4 and R 8 or R 10 , together with the atoms to which they are attached, optionally form a saturated or unsaturated 3- to 8-membered ring, wherein said 3- to 8-membered ring is optionally su bstituted with at least one heteroatom, wherein the at leaste one heteroatom is independently selected from O, S, N, and NR 12 , where R 12 is hydrogen or (Ci- C 3 )alkyl, and wherein said 3- to 8-membered ring is optionally su bstituted by at least one substituent independently selected from OH, N(R e R f ), halo, (Ci-C 6 )alkyl (C 2 -C 6 )alkenyl, (C 2 -C 6 )alkynyl, (Ci-C 6 )alk
- R 6 and R 8 together with the atoms to which they are attached, optionally form a 3- to 8-membered ring, which is optionally substituted with at least one heteroatom, wherein the at least one heteroatom is independently selected from O, S, N, and NR 13 , wherein R 13 is hydrogen or (C C 3 )alkyl, and wherein said 3- to 8-membered ring is optionally substituted by at least one substituent independently selected from OH, N(R e R f ), halo, (C C 6 )alkyl (C 2 -C 6 )alkenyl, (C 2 - C 6 )alkynyl, (C C 6 )alkoxy, and (C C 10 )alkoxyalkyl; and R 10 is hydrogen or (C C 4 )alkyl;
- X and Y are each independently present or absent, but when present, they are each
- R e and R f are each independently selected from hydrogen and (Ci-C 4 )alkyl
- Z is— (C 6 -C 14 )a lkyl, -(C 6 -Ci 4 )alkenyl, -(C 6 -Ci 4 )alkynyl, -(C 6 -Ci 4 )alkoxy, -(C 6 -C 2 o)alkoxyalkyl, -(C 3 - C 12 )cycloalkyl, -(C 6 -C 10 )aryl, -(C 7 -C 16 )alkylaryl, -(C 12 -C 16 )alkoxyaryl, -(C 6 -C 20 )arylalkyl, -(C 4 - Cio)heterocyclic, -(C 4 -Ci 0 )heteroaryl, or -(C 4 -Ci 0 )heteroaryl(Ci-Ci 6 )alkyl,
- the Z groups are optionally su bstituted with 1, 2, 3, 4, 5, 6, or 7 su bstituents; wherein the su bstituents are each independently selected from halo, halo(Ci-C 7 )alkyl, (Ci-C 7 )alkyl, cyano, N(R a R b ), (Ci-C 7 )alkoxy, (Ci-C 7 )alkoxyalkyl, (C 3 -Ci 0 )alkoxycycloalkyl, (C 3 -Ci 0 )cycloalkyl, (C 6 -Ci 0 )aryl, (C 7 -Ci 4 )alkylaryl, (C 8 -C 16 )acylarylalkyl, (C 7 -C 14 )heterocyclic, and (C 7 -C 14 )heteroaryl, wherein each su bstituent may be further optionally su bstituted
- R 2 , and R 3 are prefera bly hydrogen.
- V is preferably -C(R 4 R 5 )- or -N(R 6 )-, wherein R 4 and R 5 are preferably hydrogen, methyl, ethyl, or isopropyl, or R 4 and R 5 together with the atom to which they a re attached form cyclopropyl or cyclobutyl, R 6 is hydrogen.
- W is prefera bly present and is CR 8 R 9 , wherein R 8 a nd R 9 are prefera bly present and are hydrogen, methyl, ethyl, or isopropyl, or R 8 and R 9 together with the atom to which they are attached form cyclopropyl and cyclobutyl.
- W is prefera bly NR 10 , wherein R 10 is preferably present and is hydrogen.
- V is -C(R 4 R 5 )- and W is prefera bly present and is CR 8 R 9 , wherein R 4 and R 8 together with the atoms to which they are attached form cyclopentyl or cyclohexyl.
- V is-N(R 6 )- and W is prefera bly present and is CR 8 R 9 , wherein R 6 and R 8 together with the atoms to which they are attached form azetid inyl or pyrrolidinyl.
- V is -C(R 4 R 5 )- and W is prefera bly present and is N R 10 , wherein R 4 and R 10 together with the atoms to which they are attached form azetidinyl or pyrrolidinyl.
- R 15 and R 16 together with the atoms to which they are attached, are an alkyl or aryl ring structure optionally su bstituted with one or more heteroatoms chosen from the group azetidine, pyrrolidine, pyrrole, furan, tetrahydrofuran, thiophene, imidazolidine, imidazole, pyrazole, oxazolidine, oxazole, isoxazole, thiazole, triazole, oxadiazole, and tetrazole.
- heteroatoms chosen from the group azetidine, pyrrolidine, pyrrole, furan, tetrahydrofuran, thiophene, imidazolidine, imidazole, pyrazole, oxazolidine, oxazole, isoxazole, thiazole, triazole, oxadiazole, and tetrazole.
- R 15 and R 16 together with the atoms to which they are attached, are fused alkylaryl or aryl ring structures optionally su bstituted with one or more heteroatoms chosen from the group inda ne, benzofuran, indole, indazole, benzimidazole, benzthiophene, benzoxazole, benzisoxazole, benzthiazole, purine, tetralin, and naphthalene.
- Preferred values for Z include (C 4 -Ci 2 )alkyl, (C 4 -Ci 2 )alkenyl, or (C 4 -Ci 2 )alkylphenyl.
- the alkyl chain in the alkylphenyl group of Z has 6, 7, 8, 9, 10, 11, or 12 carbon atoms.
- Preferred values for Formula I include:
- Preferred values for of Formula I include:
- Preferred values for W V of Formula I include:
- Preferred values for ula I include:
- Preferred values for of Formula I include:
- the bonding ca n occur at any availa ble ring atom in the values containing rings, including the preferred values a bove.
- the values (rings and non-rings) may encompass any racemic, optically active or stereoisomeric form, or mixtures thereof, of the compound, such as, for example, the S,R; 5,5; R,R; or R,S diastereomers.
- a bove may also be, for exa mple, , or
- Preferred heteroatom groups for replacing carbon atoms in a ring or alkyl include O or N 10 .
- Preferred values for R 10 include hydrogen, methyl, ethyl, propyl, or isopropyl.
- Preferred compounds of the invention have formulas as shown in Table 1.
- the compounds of Formula I and methods of their use are directed to SphK enzyme inhibitors that have activity as selective inhibitors of the SphKl enzyme or the SphK2 enzyme or have activity as inhibitors of both SphKl and SphK2 enzymes.
- the present invention provides a method for inhibiting angiogenesis in a tumor, including contacting cancerous cells with an effective amount of a compound of Formula I.
- the present invention provides compositions and methods for the use of a compound of Formula I for the treatment of neoplastic disease.
- this treatment is effected by application of a compound of Formula I that are efficacious by virtue of their anti-angiogenic properties.
- the present invention provides a method for preventing or treating diseases that involve excess vascular growth, e.g., retinal degenerative diseases such as macular degeneration or diabetic retinopathy, comprising contacting the affected area with an effective amount of a compound of Formula I.
- the compound can be injected into the posterior eye in depot form.
- the present invention provides compositions and methods for the use of a compound of formula I to prevent allergic disease for example asthma.
- the asthma could be due to over production of Th2 cytokines.
- the present invention includes a method for treating subjects suffering from an allergic disease (for example, asthma).
- the invention provides a compound of Formula I for use in medical treatment for example treatment of inflammatory disease of the eye such as uveitis, scleritis, or vitritis.
- the invention provides a compound of Formula I for use in medical treatment, for example, treatment of inflammatory kindey disease such as glomerulonephritis, glomerula r injury, nephrotic syndrome, interstitial nephritis, lupus nephritis, Goodpasture's d isease, Wegener's granu lomatosis, renal vasculitis, IgA nephropathy, dia betic nephropathy, chronic allograft nephropathy and idiopathic glomerular disease.
- inflammatory kindey disease such as glomerulonephritis, glomerula r injury, nephrotic syndrome, interstitial nephritis, lupus nephritis, Goodpasture's d isease, Wegener's granu lomatosis, renal vasculitis, IgA nephropathy, dia betic nephropathy, chronic allograft
- the invention provides a compound of Formula I for use in medical treatment (for example, treatment of neoplastic disease).
- the invention provides a compound of Formula I for use in medical treatment for example treatment of fibrotic disease such as pulmonary fibrosis, renal fibrosis, cardiac fibrosis, or hepatic fibrosis.
- fibrotic disease such as pulmonary fibrosis, renal fibrosis, cardiac fibrosis, or hepatic fibrosis.
- the invention provides a compound of Formula I for use in medical treatment of acute lung injury, sepsis, capillary leak syndrome, pneumonia, ischemia reperfusion injury, acute kidney injury, dia betic nephropathy, age-related macular degeneration, dia betic retinopathy, pulmonary fibrosis, or renal fibrosis.
- the invention provides a compound of Formula I for use in enhancing the delivery of therapeutics by improving the integrity of vascular barriers (e.g., Blood Brain Barrier) in diseases where they are disrupted such as, but not limited to, cancer and Alzheimer's disease.
- vascular barriers e.g., Blood Brain Barrier
- the invention provides a compound of Formula I for use in medical treatment wherein the treatment involves the regulation of endothelial cell barrier function as a result of the inhibition of SphK enzymatic activity by a compound of Formula I.
- a compound of Formula I may be used to treat a disease or disorder that is associated with vascular leakage, such as acute lung injury, sepsis, capillary leak syndrome, pneumonia, ischemia reperfusion injury, acute kidney injury, dia betic nephropathy, age-related macular degeneration, dia betic retinopathy, pulmonary fibrosis, or renal fibrosis.
- a compound of Formula I that inhibits Sph K2 enzymatic activity can improve the barrier function of endothelial cells by causing an increase in blood levels of SIP.
- a compound of Formula I improves the barrier function of endothelial cells by selectively inhibiting SphK2. This improvement in endothelial cell barrier function by a compound of Formula I can also be achieved in the presence of increased levels of histamine and throm bin.
- the invention provides a compound of Formula I for use in medical treatment for example treatment of autoimmune diseases such as multiple sclerosis, type I dia betes, inflammatory bowel d iseases, Crohn's disease, ulcerative colitis, Grave's d isease, Addison's disease, dermatomyositis, myasthenia gravis, systemic lupus erythematosus, scleroderma, or psoriasis.
- the invention provides a method for the use of a compound of Formula I to prepare a medicament for inhibiting tumor growth, metastasis, or tumor angiogenesis.
- the invention provides a method for the use of a compound of Formula I to prepare a medicament for preventing or treating a fibrosis, sepsis, asthma, or an autoimmune disease in a mammalian species (for example, a human).
- the invention provides a method for the use of a compound of Formula I for use in medical treatment of atherosclerosis.
- the invention provides a method for the use of a compound of Formula I for use in medical treatment of hypertension for example treatment of pulmonary arterial hypertension.
- the present invention also includes pharmaceutical compositions containing a compound of Formula I. More particularly, such compounds can be formulated as pharmaceutical compositions using standard pharmaceutically acceptable carriers, fillers, solubilizing agents, and stabilizers known to those skilled in the art. For example, a pharmaceutical composition including a compound of Formula I is used to administer the appropriate compound to a subject.
- the invention provides novel intermediates and processes disclosed herein that are useful for preparing compounds of Formula I, including the generic and specific intermediates as well as the synthetic processes described herein.
- Fig. 1 exemplifies levels of sphingolipids and compound (S)-2-(3-(4-octylphenyl)-l,2,4-oxadiazol- 5-YL)pyrrolidine-l-carboximidamide (SL 080811) in U937 treated with various concentrations of compound (S)-2-(3-(4-octylphenyl)-l,2,4-oxadiazol-5-YL)pyrrolidine-l-carboximidamide as indicated.
- Fig. 2 exemplifies cultured U937 cells that were treated with vehicle or (S)-2-(3-(4-octylphenyl)- l,2,4-oxadiazol-5-YL)pyrrolidine-l-carboximidamide (SLR080811) (1 ⁇ ) for different times as indicated.
- Cells were harvested by centrifugation, lysed and the amounts of sphingolipids and SLR080811 in the lysates were measured by LC-MS as described in the Methods section. Amounts are expressed as the number of pmoles per million cells.
- the graphs are: a: SIP; b: sphingosine; c: C16:0-ceramide. Data are presented as means ⁇ SD of three independent experiments. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 (Student t-test, compared with the control (no compound treatment)).
- FIG. 3 exemplifies levels of FTY720-P and FTY720 in U397 cells treated with FTY720 and (S)-2-(3- (4-octylphenyl)-l,2,4-oxadiazol-5-YL)pyrrolidine-l-carboximidamide (SLR080811).
- Cultured U937 cells were exposed to 1 ⁇ of FTY720 and two concentrations of SLR080811 as indicated in the figure. After 2 hours of exposure, cells were harvested by centrifugation, lysed and the amounts of FTY720 and phospho-FTY720 were measured by LC-MS as described in the Methods section.
- the graphs are: a: accumulation of FTY720-P; b: accumulation of FTY720.
- Amounts are expressed as the number of pmoles per million cells. Drug and FTY720 concentrations on X axis refer to the concentration of these molecules in the culture medium. Data are presented as means ⁇ SD of three independent experiments. *p ⁇ 0.05, **p ⁇ 0.01, ***p ⁇ 0.001 (one-way ANOVA, and Bonferroni's multiple comparison test, compared with the control (no compound treatment)).
- Fig. 4 exemplifies the selectivity of (S)-2-(3-(4-octylphenyl)-l,2,4-oxadiazol-5-YL)pyrrolidine-l- carboximidamide (SLR080811) inhibition: WT, Sphkl-/- and Sphk2-/- adult mouse kidney fibroblast were exposed to 1 ⁇ SLR080811 for 2 hours. Cells were harvested by centrifugation, lysed and sphingolipids were measured by LC-MS as described in Example 5. The graphs are: (a) SIP; and (b) sphingosine. Data are presented as means ⁇ SD of three independent experiments. *p ⁇ 0.05, ***p ⁇ 0.001 (Student t-test, compared with the control (no inhibitor)).
- Fig. 5 exemplifies the viability of U937 cells treated with: (a) (S)-2-(3-(4-octylphenyl)-l,2,4- oxadiazol-5-YL)pyrrolidine-l-carboximidamide (SLR080811).
- U937 cells were exposed to various concentrations of compounds for 24 hours as indicated. The viability of the cells was measured by MTT assay as described in the Methods section. Viability is directly proportional to the amount of formazan dye produced by live cells as measured by absorbance at 570 nm. Data are presented as means ⁇ SD of three independent experiments. *p ⁇ 0.05, **p ⁇ 0.01 (one-way ANOVA, and Bonferroni's multiple comparison post test, compared with the control (no inhibitor)).
- Fig. 6 exemplifies SIP and (S)-2-(3-(4-octylphenyl)-l,2,4-oxadiazol-5-YL)pyrrolidine-l- carboximidamide (SLR080811) levels in the blood of mice injected with SLR080811. Wild type or Sphkl null or Sphk2 null mice were administered SLR080811 (dose: 10 mg/kg, intraperitoneal route). Blood samples were drawn at times 0, 1, 2, 4, 8 and 24 hours post injection. Levels of: (a) SIP; and (b) SLR080811 in WT mice in blood samples were measured by LC-MS. Data are presented as means ⁇ SD of 3-5 mice per group. *p ⁇ 0.05, **p ⁇ 0.01 (repeated measures two way ANOVA, and Bonferroni's multiple comparison test compared to ASAP time point after injection of the compound (time 0)).
- Fig. 7 exemplifies SIP levels in age-matched WT, SphkT ⁇ and Sphk2 ⁇ / ⁇ littermates. Blood were drawn from wild type, Sphkl and SphK2 null mice and the SIP levels were measured by LCMS as described in the Methods section. Data shown are independent measurements of whole blood from 4 WT, 9 SphkT ⁇ and 6 Sphk2 ⁇ / ⁇ mice. The null mice were either heterozygous or wild type at the other SphK locus. ***p ⁇ 0.001 (one-way ANOVA, and Bonferroni's multiple comparison test, compared with WT).
- Fig. 8 exemplifies SIP levels in whole blood from three rats (SD, male, 450 gm) injected (10 mpk IP) with SLP7111228 (Compound 64). SIP was measured by LC-MS. Time points ASAP, 15 min, 30 min, 60 min, 90 min, 2 hr, 4 hr, 6 hr, 22 hr.
- Table 1 shows formulas of exemplary compounds of Formula I.
- Table 2 includes the range of inhibitory constants (K
- Table 3 Chemical structure and inhibitory constants of compounds (5)-2-(3-(4-octylphenyl)- l,2,4-oxadiazol-5-YL)pyrrolidine-l-carboximidamide (SLR080811) and la.
- SLR080811 The chemical structure of compounds (S)-2-(3-(4-octylphenyl)-l,2,4-oxadiazol-5-YL)pyrrolidine-l-carboximidamide and la along with their inhibitory constants (K
- Inhibitory constants were obtained by kinetic analysis of SIP production using variable concentrations of sphingosine and a fixed concentration of ATP in presence and absence of compounds. These compounds exhibit a pattern of competitive inhibition therefore Kl's were calculated as K
- [I] / (Km'/Km-l), where [I] is the concentration of inhibitor, and Km' and Km are the Michaelis constants obtained in presence and absence of inhibitor. Measurements were carried out using [33P]-ATP as a tracer and a microplate- based scintillation proximity assay for the detection of [33P]-S1P as previously described. See Kharel, Y., Mathews, T. P., Kennedy, A. J., Macdonald, T. L. and Lynch, K. . (2011) A rapid assay for assessment of sphingosine kinase inhibitors and su bstrates. Anal. Biochem. 411, 230-235, the disclosure of which is incorporated herein.
- sphingosine kinase SphK
- SphKl sphingosine kinase type 1
- SphK2 sphingosine kinase type 2
- Sph sphingosine
- SIP sphinganine
- dhSph sphinganine
- H2Sph sphinganine 1-phosphate
- compositions that comprises “an” element means one element or more than one element.
- the term "affected cell” refers to a cell of a su bject afflicted with a disease or d isorder, which affected cell has an altered phenotype relative to a su bject not afflicted with a disease or disorder.
- Cells or tissue are "affected" by a d isease or disorder if the cells or tissue have an altered phenotype relative to the same cells or tissue in a su bject not afflicted with a disease or disorder.
- a disease or disorder is "alleviated” if the severity of a symptom of the d isease or d isorder, the frequency with which such a symptom is experienced by a patient, or both, is reduced.
- cell The terms "cell,” “cell line,” and “cell culture” may be used interchangea bly.
- a "control" cell, tissue, sample, or su bject is a cell, tissue, sample, or su bject of the same type as a test cell, tissue, sample, or su bject.
- the control may, for example, be examined at precisely or nearly the same time the test cell, tissue, sample, or su bject is examined.
- the control may also, for example, be examined at a time distant from the time at which the test cell, tissue, sample, or su bject is examined, and the results of the examination of the control may be recorded so that the recorded results may be compared with results obtained by examination of a test cell, tissue, sample, or su bject.
- the control may also be obtained from another source or similar source other than the test group or a test subject, where the test sample is obtained from a subject suspected of having a disease or disorder for which the test is being performed.
- test cell tissue, sample, or subject is one being examined or treated.
- a "pathoindicative" cell, tissue, or sample is one which, when present, is an indication that the animal in which the cell, tissue, or sample is located (or from which the tissue is obtained) is afflicted with a disease or disorder.
- a disease or disorder such as the presence of one or more breast cells in a lung tissue of an animal is an indication that the animal is afflicted with metastatic breast cancer.
- a tissue "normally comprises” a cell if one or more of the cell are present in the tissue in an animal not afflicted with a disease or disorder.
- a "detectable marker” or a “reporter molecule” is an atom or a molecule that permits the specific detection of a compound having the marker in the presence of similar compounds without a marker.
- Detectable markers or reporter molecules include, e.g., radioactive isotopes, antigenic determinants, enzymes, nucleic acids available for hybridization, chromophores, fluorophores, chemiluminescent molecules, electrochemically detectable molecules, and molecules that provide for altered fluorescence-polarization or altered light-scattering.
- a "disease” is a state of health of an animal wherein the animal cannot maintain homeostasis, and wherein if the disease is not ameliorated then the animal's health continues to deteriorate.
- a "disorder" in an animal is a state of health in which the animal is able to maintain homeostasis, but in which the animal's state of health is less favorable than it would be in the absence of the disorder. Left untreated, a disorder does not necessarily cause a further decrease in the animal's state of health.
- autoimmune disease is a disease or disorder arising from and directed against an individual's own tissues.
- autoimmune diseases or disorders include, but are not limited to arthritis (rheumatoid arthritis, juvenile rheumatoid arthritis, osteoarthritis, psoriatic arthritis), Caplan's Syndrome, Felty's Syndrome, psoriasis, dermatitis, Sjorgren's Syndrome, Still's Disease,
- polymyositis/dermatomyositis toxic epidermal necrolysis, systemic scleroderma and sclerosis, responses associated with inflammatory bowel disease, Crohn's disease, ulcerative colitis, respiratory distress syndrome, adult respiratory distress syndrome (ARDS), meningitis, encephalitis, uveitis, colitis, glomerulonephritis, allergic conditions, eczema, asthma, conditions involving infiltration of T cells and chronic inflammatory responses, atherosclerosis, autoimmune myocarditis, leukocyte adhesion deficiency, systemic lupus erythematosus (SLE), juvenile onset diabetes, multiple sclerosis, allergic encephalomyelitis, immune responses associated with acute and delayed hypersensitivity mediated by cytokines and T-lymphocytes, tuberculosis, sarcoidosis, granulomatosis including Wegener's granulomatosis, agranulocytosis, vasculitis (including
- ITP thrombocytopenic purpura
- OTP thrombotic throbocytopenic purpura
- thrombocytopenia autoimmune disease of the testis and ovary including autoimune orchitis and oophoritis, primary hypothyroidism; autoimmune endocrine diseases including autoimmune thyroiditis, chronic thyroiditis (Hashimoto's Thyroiditis), subacute thyroiditis, idiopathic hypothyroidism, Addison's disease, Grave's disease, autoimmune polyglandular syndromes (or polyglandular endocrinopathy syndromes), Type I diabetes also referred to as insulin-dependent diabetes mellitus (IDDM) and
- IDDM insulin-dependent diabetes mellitus
- Sheehan's syndrome autoimmune hepatitis, lymphoid interstitial pneumonitis (HIV), bronchiolitis obliterans (non-transplant) vs NSIP, Guillain-Barre' syndrome, large vessel vasculitis (including polymyalgia rheumatica and giant cell (Takayasu's) arteritis), medium vessel vasculitis (including Kawasaki's disease and polyarteritis nodosa), ankylosing spondylitis, Berger's disease (IgA nephropathy), rapidly progressive glomerulonephritis, primary biliary cirrhosis, Celiac sprue (gluten enteropathy), cryoglobulinemia, amyotrophic lateral sclerosis (ALS), coronary artery disease etc.
- HIV lymphoid interstitial pneumonitis
- bronchiolitis obliterans non-transplant
- NSIP Guillain-
- An "inflammatory disease” may be any automimmune disease, as well as include, but not be limited to: ulcerative colitis, and Crohn's disease; cardiovascular diseases such as ischemic cardiac disease and heart failure; cerebrovascular diseases; kidney diseases, including glomerulonephritis, glomerular injury, nephrotic syndrome, interstitial nephritis, lupus nephritis, Goodpasture's disease, Wegener's granulomatosis, renal vascu litis, IgA nephropathy and idiopathic glomerular disease;
- dia betes dia betes complications such as retinopathy, nephropathy, nerve disease, and coronary arterial disease; skin diseases, including allergic skin disease, psoriasis, atopic dermatitis, contact sensitivity a nd acne; obesity; nephritis; hepatitis; cancer; Alzheimer's disease; inflammatory d iseases that are caused by inflammatory cytokines; skin diseases such as allergic skin d iseases; chondrocalcinosis; gout; rheumatic fever and eiter's Disease.
- Immuno cell(s) include, but are not limited to, lymphocytes, (including CD4 + T cells, CD8 + T cells, Natural Killer T cells, and B cells), mast cells, basophils, macrophaged, dendritic cells, monocytes, eosinophils, neutrophils, or any other cell type that functions within the immune system.
- Vascular permeability refers to the capacity of small molecules (e.g., ions, water, nutrients), large molecules (e.g., proteins and nucleic acids) or even whole cells (lymphocytes on their way to the site of inflammation) to pass through a blood vessel wall.
- Diseases and d isorders characterized by undesira ble vascular permea bility include, for example, edema associated with brain tumors, ascites associated with malignancies, Meigs' syndrome, lu ng inflammation, nephrotic syndrome, pericardial effusion and pleural effusion.
- a "functional" molecule is a molecule in a form in which it exhibits a property by which it is characterized.
- a functional enzyme is one that exhibits the characteristic catalytic activity by which the enzyme is characterized.
- inhibitor refers to the a bility of a d isclosed compound to reduce or impede a described function. Inhibition is by at least 10%, prefera bly by at least 25%, more prefera bly by at least 50%, even more prefera bly by at least 75%, and most prefera bly, the function is inhibited by at least 95%.
- selective refers to the a bility of the disclosed compounds to inhibit one of the sphingosine kinase 1 or sphingosine kinase 2 (SphKl & SphK2) enzymes and not the other enzyme.
- the selective compound will have a K
- an "effective amount” means an amount sufficient to produce a selected effect.
- an effective amount of a sphingosine kinase 1 or sphingosine kinase 2 (SphKl & SphK2) inhibitor is an amount that inhibits su bstrate (sphingosine) binding of the sphingosine kinases and thereby the conversion of sphingosine to SIP and sphinganine to d hSlP.
- the term "instructional material” includes a pu blication, a record ing, a diagram, or any other medium of expression that can be used to communicate the usefulness of the disclosed compounds in the kit for effecting alleviation of the various diseases or disorders recited herein.
- the instructional material may describe one or more methods of alleviating the diseases or disorders in a cell or a tissue of a mammal.
- the instructional material of the kit may, for example, be affixed to a container that contains a disclosed compound or be shipped together with a container which contains the identified compound. Alternatively, the instructional material may be shipped separately from the container with the intention that the instructional material and the compound be used cooperatively by the recipient.
- parenteral means not through the alimentary canal but by some other route such as subcutaneous, intramuscular, intraspinal, or intravenous.
- purified and similar terms relate to the isolation of a molecule or compound in a form that is substantially free (at least 75% free, preferably 90% free, and most preferably at least 95% free) from other components normally associated with the molecule or compound in a native environment.
- purified does not necessarily indicate that complete purity of the particular molecules achieved during the process.
- a “very pure” compound refers to a compound that is greater than 90% pure.
- a “highly purified” compound refers to a compound that is greater than 95% pure.
- sample refers preferably to a biological sample from a subject, including, but not limited to, normal tissue samples, diseased tissue samples, biopsies, blood, saliva, feces, semen, tears, and urine.
- a sample can also be any other source of material obtained from a subject, which contains cells, tissues, or fluid of interest.
- a sample can also be obtained from cell or tissue culture.
- Standard refers to something used for comparison.
- a standard can be a known standard agent or compound that is administered or added to a control sample and used for comparing results when measuring said compound in a test sample.
- Standard can also refer to an "internal standard,” such as an agent or compound which is added at known amounts to a sample and is useful in determining such things as purification or recovery rates when a sample is processed or subjected to purification or extraction procedures before a marker of interest is measured.
- a "subject" of analysis, diagnosis, or treatment is an animal. Such animals include mammals, preferably is a human.
- a “therapeutic” treatment is a treatment administered to a subject who exhibits signs of pathology for the purpose of diminishing or eliminating those signs.
- a “therapeutically effective amount” of a compound is that amount of compound which is sufficient to provide a beneficial effect to the subject to which the compound is administered.
- the term “treating” includes prophylaxis of the specific disorder or condition, or alleviation of the symptoms associated with a specific disorder or condition or preventing or eliminating said symptoms.
- the d isclosed compou nds are generally named according to the l UPAC or CAS nomenclature system. Abbreviations that are well known to one of ordinary skill in the art may be used (e.g., "Ph” for phenyl, “Me” for methyl, “Et” for ethyl, “h” for hour or hours, “r.t.” for room temperature, “TH F” for tetrahydrofuran, and “rac” for racemic mixture).
- radicals su bstituents, and ranges, are for illustration purposes only; they do not exclude other defined values or other values within defined ranges for the radicals and su bstituents.
- the disclosed compounds include compounds of Formula I having any com bination of the exemplary values, preferred values, and more preferred values described herein.
- (C C 6 )alkyl refers to an alkyl su bstituent containing from 1 to 6 carbon atoms.
- (C 3 -C 6 )cycloalkyl means a saturated hydrocarbyl ring containing from 3 to 6 carbon ring atoms.
- a single prefix attached to a multiple-component su bstituent applies to all of the components that follow the prefix.
- the term "arylalkyi" contains two components: aryl and alkyl.
- (C 6 -C 20 )arylalkyl means that the total num ber of carbon atoms for both the aryl and alkyl su bstituents ranges from 6 to 20 carbon atoms.
- heteroarylalkyl contains two components: heteroaryl and alkyl.
- (C 4 - Cio)heteroaryl(C Ci 6 )alkyl refers to a heteroaryl group containing 4 to 10 carbon atoms appended to an alkyl group containing 1 to 16 carbon atoms.
- the dash(s) indicates the portion of the moiety that has the free valence(s). If no dash(s) is included for a multiple-component su bstituent, the moiety is appended to the parent molecular moiety through the first listed component. For example, an arylalkyi su bstituent is appended to a parent molecule through the aryl group, whereas an alkylaryl su bstituent is appended to a parent molecule through the alkyl group.
- halogen or "halo” includes bromo, chloro, fluoro, and iodo.
- halo indicates that the su bstituent to which the prefix is attached is su bstituted with one or more independently selected halogen radicals.
- haloalkyl refers to an alkyl radical bearing at least one halogen su bstituent, non-limiting examples include, but are not limited to, chloromethyl, fluoroethyl, trifluoromethyl, and the like.
- alkyl refers to a branched or linear hydrocarbyl group. Non-limiting examples include, but are not limited to, methyl, ethyl, n-propyl, iso-propyl, butyl, iso-butyl, sec-butyl, ieri-butyl, pentyl, hexyl, heptyl, octyl, and the like.
- alkenyl refers to an olefinically unsaturated branched or linear hydrocarbyl group having at least one dou ble bond.
- alkenyl groups refer to ethylenically unsaturated groups which may be linear or have branches a nd which include, but are not limited to, 1-propenyl, 2-propenyl, 1,3-butadienyl, 1-butenyl, pentenyl, hexenyl, heptenyl, octenyl, and the like.
- alkynyl refers to hyd rocarbyl groups having at least one carbon-carbon triple bond, which grou p may be linear or branched and which include, but are not limited to, 1-propynyl, 2-propynyl, 1-butynyl, 2-butynyl, 3-butynyl, 1-pentynyl, 2-pentynyl, 3-pentynyl, 4- pentynyl, 1- hexynyl, 2-hexynyl, 3-hexynyl, 4-hexynyl, 5-hexynyl, and the like.
- alkoxy refers to an alkyl group, such as described a bove, attached through an oxygen atom.
- alkoxy can be methoxy, ethoxy, propoxy, isopropoxy, butoxy, iso-butoxy, sec-butoxy, pentoxy, 3-pentoxy, hexyloxy, heptoxy, octoxy, and the like.
- alkoxyalkyl can be methoxy methyl, methoxy ethyl, ethoxy methyl, ethoxy ethyl, and the like.
- cycloalkyl includes grou ps having one ring or multiple rings. Non-limiting examples include be cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclooctyl, adamantyl, and the like.
- su bstituted refers to zero, one, two, three, four, five, six, seven, or more su bstituents, wherein the su bstituents are each independently selected. Each of the independently selected su bstituents may be the same or different than other su bstituents.
- Non-limiting examples of such su bstituents include halo, halo(Ci-Ci 0 )alkyl, OH, cyano, amino (-N a b ), (Ci-C 6 )alkyl, (Ci-C 2 o)alkoxy, (C 2 -C )alkoxyalkyl, (C 3 -Ci 2 )cycloalkyl, (C 6 -Ci 0 )aryl, (C 7 - C 30 )alkylaryl, (C 2 -Ci 0 )heterocyclic, or (C 4 -Ci 0 )-heteroaryl; wherein one or more of the carbon atoms in the alkyl groups can be independently replaced with non-peroxide oxygen, sulfur, or N R C ; where each R a , R b , or R c is independently hydrogen or (Ci-C 7 )alkyl.
- ring refers to a cyclic structure of its constituent atoms. Ring sizes may vary, but typically range from 3 to 8 atoms.
- aryl refers to a mono or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, phenyl, benzyl, benzimidazole, naphthyl, tetrahydronaphthyl, indanyl, indenyl, and the like.
- su bstituted aryl includes aryl compounds having zero, one, two, three, or four su bstituents
- a su bstituted aryl includes aryl compounds having one, two, three, or four su bstituents, wherein the su bstituents include groups such as, for example, alkyl, halo, amino, or those su bstituents listed herein.
- arylalkyl “alkylaryl,” or “aralkyl” refers to an alkyl group su bstituted and/or linked with at least one mono or bicyclic carbocyclic ring system having one or two aromatic rings including, but not limited to, a group such as phenyl, naphthyl, tetrahydronaphthyl, indanyl, indenyl, a nd the like.
- arylalkyl and alkylaryl include benzyl, phenyl ethyl, and the like.
- alkoxyaryl can be methoxy phenyl, ethoxy phenyl, propoxy naphthyl, isopropoxy naphthyl, and the like.
- alkoxycycloalkyl can be methoxy cyclopropyl, ethoxy cyclopropyl, propoxy cyclobutyl, isopropoxy cyclobutyl, and the like.
- acylarylalkyl can be -C(0)-phenyl-methyl, - C(0)-phenyl-ethyl, a nd the like.
- heterocycle or “heterocyclic group” refers to an optionally su bstituted mono- or bicyclic carbocyclic ring system containing one, two, three, or more heteroatoms (optionally in each ring) wherein the heteroatoms are non-peroxide oxygen, sulfur, and nitrogen (e.g., N C ).
- heteroaryl refers to an optionally su bstituted mono- or bicyclic carbocyclic ring system containing one, two, or three heteroatoms (optionally in each ring) wherein the
- heteroatoms are non-peroxide oxygen, sulfur, and nitrogen (e.g., NR C ).
- Non-limiting examples of heteroaryl groups include furyl, oxadiazolyl, thienyl, pyridyl, and the like.
- heteroarylalkyl can be furyl methyl, oxadiazolyl methyl, furyl ethyl, oxadiazolyl ethyl, and the like.
- bicyclic represents either a n unsaturated or saturated sta ble bridged or fused bicyclic carbon ring.
- the bicyclic ring may be attached at any carbon atom that affords a sta ble structure.
- a bicyclic ring system can have from a bout 7 to a bout 12 atoms in the ring system.
- the term includes, but is not limited to, naphthyl, dicyclohexyl, dicyclohexenyl, and the like.
- a bsent means that the referenced varia ble/su bstituent may not be present in the structu re. For example, if W is "a bsent" in Formula I, then W is not present in that pa rticular structure of Formula I. In some situations, if a particular varia ble/su bstituent is "a bsent" in Formula I, a dou ble bond or a triple bond may be present in that particular structure of Formula I.
- V, W, X, Y, and Z in Formula I need not be directly connected by a single bond but may be connected via any of the atoms in the ring structures described for V, W, X, and Y" means that should any of V, W, X, and Y in Formula I form a ring structure with an adjacent atom or form its own ring structure than that ring structure(s) may be connected to any adjacent moieties within Formula I via any atom within that ring structure(s).
- V is N 6 a nd W is CR 8 R 9
- R 6 and R 8 together with the atoms to which they are attached, may optionally form a ring.
- That V-W ring therefore, may have, for example, the following generic and exemplary structure:
- R 14 and R 15 together with the atoms to which they are attached, may form, for example, an aryl ring optionally su bstituted with at least one heteroatom selected from O, S, N, or N R 17 .
- That Y ring therefore, may have, for example, the following generic and exemplary structure:
- pharmaceutically accepta ble carrier includes any of the standard pharmaceutical carriers, such as a phosphate buffered saline solution, hydroxypropyl beta-cyclodextrins
- HO-propyl beta cyclodextrins water, emulsions such as an oil/water or water/oil emulsion, and various types of wetting agents.
- emulsions such as an oil/water or water/oil emulsion
- wetting agents various types of wetting agents.
- the term also encompasses any of the agents approved by a regu latory agency of the U.S. Federal government or listed in the US Pharmacopeia for use in animals, including humans.
- salts refers to salts which retain the biological effectiveness and properties of the disclosed compounds and which are not biologically or otherwise undesira ble.
- the disclosed compounds are capa ble of forming acid- or base-addition salts by virtue of the presence of amino or carboxyl grou ps or groups similar thereto.
- Such salts include as one example, but are not limited to, acid-addition salts from acids having the formula HA, where A is comprised of the group chloride, bromide, sulfate, acetate, benzoate, and tartrate.
- prodrug refers to derivatives of the compounds of the invention which have chemically or meta bolically cleava ble groups and become, under physiological conditions, the compounds of the invention which are pharmaceutically active in vivo. Fu rther, the prodrug is converted in both sufficient amounts and in a time frame that allows the active compound of the invention to accumulate in sufficient amounts to provide an efficacious effect.
- a prodrug of a compound may be formed in a conventional manner by reaction of a functional group of the compound (such as an amino, hydroxy or carboxy group). Prodrugs often offer advantages of solu bility, tissue compatibility, or delayed release in mammals.
- Prodrugs include acid derivatives well known to practitioners of the art, such as, for example, esters prepared by reaction of the parent acidic compound with a suita ble alcohol, or amides prepared by reaction of the parent acid compound with a suita ble amine.
- Examples of prodrugs include, but are not limited to, acetate, formate, benzoate, carbamate, or other acylated derivatives of alcohol or amine functional groups within the compounds of the invention.
- the d isclosed compou nds may exist in tautomeric forms and the invention includes both
- the terms 16:0, 18:0, 18: 1, 20:4, or 22:6 hydrocarbon refers to a branched or straight alkyl or alkenyl group, wherein the first integer represents the total num ber of carbons in the group and the second integer represent the nu mber of dou ble bonds in the group.
- the disclosed compou nds can contain one or more asymmetric centers in the molecule.
- any structure that does not designate the stereochemistry is to be understood as em bracing all the various optical isomers, as well as racemic mixtures thereof.
- the d isclosed compounds having chiral centers may exist, and be isolated, in optically active and racemic forms. It is to be understood that the d isclosed compou nds encompass any racemic, optically active or stereoisomeric form, or mixtures thereof, of the compound, which possess the useful properties described herein, such as the S,R; 5,5; R,R; or R,S diastereomers.
- optically active forms for example, resolution of the racemic form by recrystallization techniques, synthesis from optically- active starting materials, chiral synthesis, or by chromatographic separation using a chiral stationary phase
- sphingosine kinase activity using the standard tests described herein, or using other similar tests which are well known in the art.
- some compounds may exhibit polymorphism.
- SphK inhibitors of the invention include, but a re not limited to, anti-angiogenesis, treating neoplastic d isease, treating autoimmune disorders, treating disease characterized by inflammation, treating diseases characterized by fibrosis, and treating vascular injury, such as acute lung injury, sepsis, capillary and vascular leak syndromes, pneumonia, ischemia reperfusion injury, acute kidney injury, as well as enhancing the delivery of therapeutics by improving the integrity of vascular barriers (e.g., Blood Brain Barrier) in d iseases where they are disru pted such as, but not limited to cancer and Alzheimer's disease.
- the method of treating any of the foregoing conditions may include administration of an antagonist of any one, or combination thereof, of S1P(1), S1P(2), S1P(3), S1P(4), and S1P(5).
- the Sph K inhibitors of the invention may be used to treat autoimmu ne and infla mmatory conditions, i.e., immunomodulate components of the immune system.
- the SphK inhibitors of the invention may affect the cell signaling events associated with, but not limited to, the following interleukins, cytokines, and
- immunomodulators a) mem bers of the interleukin-1 (I L-1) family; b) interleukin 2 (I L-2); c) interleukin 4 (IL-4); d) interleukin 5 (IL-5); e) interleukin-6 (IL-6); f) interleukin-12 (IL-12); g) interleukin 13 (I L-13); h) interleukin-23 (IL-23); i) tumor necrosis factor (TNF) a lpha; and j) interferon gamma.
- I L-1 interleukin-1
- I L-2 interleukin 2
- IL-4 interleukin 4
- IL-5 interleukin 5
- IL-6 interleukin-6
- f interleukin-12
- a SphK inhibitor of the invention may be used to treat a disease that is at least in part characterized by the over-expression or u ndesira ble cell-signaling activities mediated by any of the a bove factors.
- the presently d isclosed su bject matter provides a method for preventing, treating, managing, and/or ameliorating an autoimmune or inflammatory disorder or one or more symptoms thereof, said method comprising administering to a su bject in need thereof a prophylactically and/or therapeutically effective amount of a compound of the presently disclosed su bject matter and a prophylactically or therapeutically effective amount of one or more immunomodulatory agents.
- the compounds of Formu la I are also useful for the treatment of diseases or disorders that are associated with excessive vascular permea bility.
- a method of treating or preventing these or any other disease associated with an increase in vascular permea bility or edema should be beneficial to overall patient outcome in situations such as inflammation, allergic d iseases, cancer, cerebral stroke, myocardial infarction, pulmonary and cardiac insufficiency, renal failure, and retinopathies, to name a few.
- edema is a general consequence of tissue hypoxia
- inhibition of vascular leakage represents a potential approach to the treatment of tissue hypoxia.
- interruption of blood flow by pathologic conditions such as thrombus formation
- medical intervention such as cardioplegia, organ transplantation, and angioplasty
- Ischemia/reperfusion injury following stroke and myocardial infarction is also characterized by vascular permeability and edema.
- a deficit in tissue perfusion leads to persistent postishemic vasogenic edema, which develops as a result of increased vascular permeability.
- Tissue perfusion is a measure of oxygenated blood reaching the given tissue due to the patency of an artery and the flow of blood in an artery. Tissue vascularization may be disrupted due to blockage, or alternatively, it may result from the loss of blood flow resulting from blood vessel leakage or hemorrhage upstream of the affected site.
- post-pump syndrome a worsening of condition
- An arterial blockage may cause a reduction in the flow of blood, but even after the blockage is removed and the artery is opened, if tissue reperfusion fails to occur, further tissue damage may result.
- disruption of a clot may trigger a chain of events leading to loss of tissue perfusion, rather than a gain of perfusion.
- Additional diseases and disorders characterized by undesirable vascular permea bility include, for example, infectious and non-infectious diseases that may result in a cytokine storm.
- a cytokine storm can be precipitated by a number of infectious and non-infectious diseases including, for example, graft versus host disease (GVHD), adult respiratory distress syndrome (A DS), sepsis, avian influenza, smallpox, and systemic inflammatory response syndrome (SIRS).
- GVHD graft versus host disease
- a DS adult respiratory distress syndrome
- SIRS systemic inflammatory response syndrome
- Table 2 includes: Range of inhibitory constants (K
- Salts from inorganic bases include but are not limited to, sodium, potassium, lithium, ammonium, calcium, and magnesium salts.
- Salts derived from organic bases include, but are not limited to, salts of primary, secondary, and tertiary amines, such as alkyl a mines, dialkyi amines, trialkyi amines, su bstituted alkyl amines, di(su bstituted alkyl) a mines, tri(su bstituted alkyl) amines, alkenyl amines, dialkenyl amines, trialkenyl amines, su bstituted alkenyl amines, di(su bstituted alkenyl) amines, tri(su bstituted alkenyl) amines, cycloalkyi amines, di(cycloalkyl)
- amines diheterocyclic amines, triheterocyclic amines, mixed di- and tri-amines where at least two of the su bstituents on the amine are different and are alkyl, su bstituted alkyl, alkenyl, su bstituted alkenyl, cycloalkyi, su bstituted cycloalkyi, cycloalkenyl, su bstituted cycloalkenyl, aryl, heteroaryl, or heterocyclic, and the like.
- amines where the two or three su bstituents, together with the amino nitrogen, form a heterocyclic or heteroaryl group.
- Non-limiting examples of amines include, isopropylamine, trimethyl amine, diethyl amine, tri(iso-propyl) amine, tri(n-propyl) amine,
- carboxylic acid derivatives would be useful, for example, carboxylic acid amides, including carboxamides, lower (e.g., C C 6 ) alkyl carboxamides, d ialkyi carboxamides, and the like.
- compositions of Formula I are sufficiently basic or acidic to form sta ble nontoxic acid or base salts
- preparation and administration of the compounds as pharmaceutically accepta ble salts may be appropriate.
- pharmaceutically accepta ble salts are organic acid addition salts formed with acids that form a physiological accepta ble anion, for example, tosylate, methanesulfonate, acetate, citrate, ma lonate, tartarate, succinate, benzoate, ascorbate, a- ketoglutarate, and a-glycerophosphate.
- Inorganic salts may also be formed, including hydrochloride, sulfate, nitrate, bicarbonate, and carbonate salts.
- the compounds of the formulas a bove include all enantiomers thereof.
- salts may be obtained using standard procedures well known in the art, for example by reacting a sufficiently basic compound such as an amine with a suita ble acid affording a physiologically accepta ble anion.
- a sufficiently basic compound such as an amine
- a suita ble acid affording a physiologically accepta ble anion.
- Alkali metal for example, sodium, potassium, or lithium
- alkaline earth metal for example, calcium
- the compounds of Formu la I ca n be formulated as pharmaceutical compositions and administered to a mammalian host, such as a human patient in a variety of forms adapted to the chosen route of administration, e.g., orally or parenterally, by intravenous, intramuscular, topical, or su bcutaneous routes.
- the compounds of Formula I may be systemically administered, e.g., orally, in com bination with a pharmaceutically accepta ble vehicle such as an inert diluent, or an assimila ble edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into ta blets, or may be incorporated d irectly with the food of the patient's diet.
- a pharmaceutically accepta ble vehicle such as an inert diluent, or an assimila ble edible carrier. They may be enclosed in hard or soft shell gelatin capsules, may be compressed into ta blets, or may be incorporated d irectly with the food of the patient's diet.
- the active compound may be combined with one or more excipients and used in the form of ingestible ta blets, buccal ta blets, troches, capsules, elixirs, suspensions, syrups, wafers, and the like.
- compositions and preparations should contain at least a bout 0.1% of active compound.
- the percentage of the compositions and preparations may, of course, be varied and may conveniently be between a bout 2 to a bout 60% of the weight of a given unit dosage form.
- the amount of active compound in such therapeutically useful compositions is such that an effective dosage level will be obtained.
- the ta blets, troches, pills, capsules, and the like may also contain the following: binders such as gum tragacanth, acacia, corn starch, gelatin, and the like; excipients such as dicalcium phosphate; a disintegrating agent such as corn starch, potato starch, alginic acid, and the like; a lu bricant such as magnesium stearate; and a sweetening agent such as sucrose, fructose, lactose, or aspartame, or a flavoring agent such as peppermint, oil of wintergreen, or cherry flavoring may be added.
- binders such as gum tragacanth, acacia, corn starch, gelatin, and the like
- excipients such as dicalcium phosphate
- a disintegrating agent such as corn starch, potato starch, alginic acid, and the like
- a lu bricant such as magnesium stearate
- the unit dosage form When the unit dosage form is a capsule, it may contain, in addition to materials of the a bove type, a liquid carrier, such as a vegetable oil or a polyethylene glycol. Various other materials may be present as coatings or to otherwise modify the physical form of the solid unit dosage form. For instance, tablets, pills, or capsules may be coated with gelatin, wax, shellac, sugar, and the like.
- a syrup or elixir may contain the active compound, sucrose, or fructose as a sweetening agent, methyl and propylparabens as preservatives, a dye and flavoring such as cherry or orange flavor.
- any material used in preparing any unit dosage form should be pharmaceutically acceptable and substantially non-toxic in the amounts employed.
- the active compound may be incorporated into sustained-release preparations and devices.
- a compound of Formula I or a pharmaceutical composition containing it may also be administered intravenously or intraperitoneally by infusion or injection. Solutions of the active compound or its salts can be prepared in water, optionally mixed with a nontoxic surfactant.
- Dispersions can also be prepared in glycerol, liquid polyethylene glycols, triacetin, and mixtures thereof and in oils. Under ordinary conditions of storage and use, these preparations contain a preservative to prevent the growth of microorganisms.
- Exemplary pharmaceutical dosage forms for injection or infusion can include sterile aqueous solutions or dispersions or sterile powders comprising the active ingredient which are adapted for the extemporaneous preparation of sterile injectable or infusible solutions or dispersions, optionally encapsulated in liposomes.
- the liquid carrier or vehicle can be a solvent or liquid dispersion medium comprising, for example, water, ethanol, a polyol (for example, glycerol, propylene glycol, liquid polyethylene glycols, and the like), vegetable oils, nontoxic glyceryl esters, and mixtures thereof.
- the proper fluidity can be maintained, for example, by the formation of liposomes, by the maintenance of the required particle size in the case of dispersions or by the use of surfactants.
- the prevention of the action of microorganisms can be brought a bout by various antibacterial and antifungal agents, for example, parabens, chlorobutanol, phenol, sorbic acid, thimerosal, and the like.
- isotonic agents for example, sugars, buffers, or sodium chloride.
- Prolonged absorption of the injectable compositions can be brought about by the use in the
- compositions of agents delaying absorption for example, aluminum monostearate and gelatin.
- Sterile injecta ble solutions are prepared by incorporating a compound of Formula I in the required amount in the appropriate solvent with various of the other ingredients enumerated above, as required, followed by filter sterilization.
- the preferred methods of preparation are vacuum drying and the freeze drying techniques, which yield a powder of the active ingredient plus any additional desired ingredient present in the previously sterile-filtered solutions.
- a compound of Formula I may be applied in pure form, e.g., when they are liquids. However, it will generally be desira ble to administer them to the skin as compositions or formulations, in com bination with a dermatologically accepta ble carrier, which may be a solid or a liquid.
- Exemplary solid carriers include finely divided solids such as talc, clay, microcrystalline cellulose, silica, alumina, and the like.
- Useful liquid carriers include water, alcohols, or glycols or water- alcohol/glycol blends, in which the present compounds can be dissolved or d ispersed at effective levels, optionally with the aid of non-toxic surfactants.
- Adjuvants such as fragrances a nd additional antimicrobial agents can be added to optimize the properties for a given use.
- the resultant liquid compositions can be applied from a bsorbent pads, used to impregnate bandages and other d ressings, or sprayed onto the affected area using pump-type or aerosol sprayers.
- Thickeners such as synthetic polymers, fatty acids, fatty acid salts a nd esters, fatty alcohols, modified celluloses, or modified mineral materials can also be employed with liquid carriers to form spreada ble pastes, gels, ointments, soaps, and the like, for application directly to the skin of the user.
- Examples of useful dermatological compositions which can be used to deliver the compounds of Formula I to the skin are known to the art; for example, see Jacquet et al. (U.S. Pat. No. 4,608,392), Geria (U.S. Pat. No. 4,992,478), Smith et al. (U.S. Pat. No. 4,559, 157), and Wortzman (U.S. Pat. No. 4,820,508), the disclosures of which are incorporated herein.
- Useful dosages of the compounds of Formula I can be determined by comparing their in vitro activity and in vivo activity in a nimal models. Methods for the extrapolation of effective dosages in mice, and other animals, to hu mans are known to the art; for exa mple, see U.S. Pat. No. 4,938,949, the disclosure of which is incorporated herein.
- the concentration of the compound(s) of Formula I in a liquid composition will be from a bout 0.1 to a bout 25 weight percent, preferably from a bout 0.5-10 weight percent.
- concentration in a semi-solid or solid composition such as a gel or a powder will be a bout 0.1-5 weight percent, prefera bly a bout 0.5-2.5 weight percent, based on the total weight of the composition.
- the amount of a compound of Formula I used in treatment will vary not only with the particular compound selected but also with the route of administration, the nature of the condition being treated, and the age and condition of the patient, and will be ultimately at the discretion of the attendant physician or clinician.
- a suita ble dose will be in the range of from a bout 0.5 to a bout 100 mg/kg, e.g., from about 10 to a bout 75 mg/kg of body weight per day, such as 3 to a bout 50 mg per kilogram body weight of the recipient per day, prefera bly in the range of 6 to 90 mg/kg/day, most preferably in the range of 15 to 60 mg/kg/day.
- the compound is conveniently administered in unit dosage form; for example, containing 5 to 1000 mg, conveniently, 10 to 750 mg, most conveniently, 50 to 500 mg, of active ingredient per unit dosage form.
- a compound of Formula I as the active ingredient, should be administered to achieve peak plasma concentrations of the active compound of from a bout 0.5 to a bout 75 ⁇ , preferably, a bout 1 to 50 ⁇ , most prefera bly, a bout 2 to a bout 30 ⁇ .
- This may be achieved, for example, by the intravenous injection of a 0.05 to 5% solution of the active ingredient, optionally in saline, or orally administered as a bolus containing a bout 1-10 mg of the active ingredient.
- Desira ble blood levels may be maintained by continuous infusion to provide a bout 0.01-5.0 mg/kg/hr or by intermittent infusions containing a bout 0.4-15 mg/kg of the active ingredient(s).
- the desired dose may conveniently be presented in a single dose or as divided doses administered at appropriate intervals, for example, as two, three, four, or more su b-doses per day.
- the su b-dose itself may be further divided, e.g., into a num ber of discrete loosely spaced administrations; such as multiple inhalations from an insufflator or by application of a plurality of drops into the eye.
- THF was dried over activated molecular sieves (4 A) prior to use. All other reagents were purchased from Acros chemicals and Aldrich chemicals. Except as indicated otherwise, reactions were monitored by thin layer chromatography (TLC) using 0.25 mm Whatman precoated silica gel plates. Flash chromatography was performed with the indicated solvents and Dynamic Adsorbents silica gel (particle size 0.023 - 0.040 mm). Proton ( 1 H) and carbon ( 13 C) NMR spectra were recorded on a Varian Unitylnova 500/51 or Varian Unitylnova 300/54 at 300K unless otherwise noted.
- LCMS identification and purity utilized a binary gradient starting with 90% A and 10% B and linearly increasing to 100% B over the course of 6 min, followed by an isocratic flow of 100% B for an additional 3 min. A flow rate of 0.5 mL / min was maintained throughout the HPLC method. The purity of all products was determined by integration of the total ion count (TIC) spectra and integration of the ultraviolet (UV) spectra at 214 nm. Retention times are abbreviated as t R ; mass to charge ratios are abbreviated as m/z.
- TIC total ion count
- UV ultraviolet
- the solid was reconstituted with CHCI 3 and filtered through a fine glass fritted funnel in order to remove excess ammonium chloride, and the filtrate was again evacuated to dryness.
- the material was then recrystallized in Et 2 0 to yield the pure amidine hydrochloride salt.
- the yields varied greatly depending upon substrate, because amidine formation is dependent upon the equilibrium ratio between nitrile and imidate established under the sodium methoxide conditions.
- Tetrabutylammonium Fluoride from Acylated Amide Oximes To a solution of O-acyl amidoxime (1.0 eq.) in THF (0.1 M) at r.t. was added a 1.0 M solution of TBAF in THF (1.0 eq.) and stirred for 1 h. The reaction was evaporated to dryness and immediately purified by flash chromatography.
- Trifluoroacetic acid (15 equiv) was added to a solution of Boc- protected amine (1 equiv) in CH 2 CI 2 (0.2 M solution). The reaction mixture was then stirred at r.t. for 3 h. At this time, TLC showed complete conversion of starting material. The organic solvent was removed under reduced pressure. The resulting residue was partitioned between diethyl ether and water. The aqueous solution was adjusted to pH 14 by adding 10% NaOH solution. The solution was then extracted with ether and the combined organic layers were washed with brine, dried over Na 2 S0 4, filtered, and concentrated under reduced pressure to provide the desired product.
- methyl 4-dodecylbenzoate (lc): To a stirring solution of anhydrous methanol (1.7 mL) at 0 C, acyl chloride (0.25 mL, 3.440 mmol) was added dropwise. The mixture was stirred for 10 min. at 0 C. To the mixture, acid lb (0.500 g, 1.722 mmol) was added in one portion and stirred. The reaction was slowly heated to reflux overnight.
- the reaction was then washed 2x with hexanes (equal to the volume of dioxane), and then the aqueous layer was acidifies with 1M HCI (until a pH lower then 2 is established).
- the acidic aqueous solution was then extracted 3x with EtOAc (equal to the volume of the aqueous layer), dried with Na 2 S0 4 , and concentrated to white solid.
- the N-Boc serine, PyBOP (1.1 eq.), and Weinreb salt (1.1 eq.) were dissolved in CH 2 CI 2 (0.6 M) at 0 °C and TEA (1.1 eq.) was added.
- the reaction was warmed to r.t. and stirred for 4 h.
- the reaction was then quenched with 1 M HCI (lOx the volume of CH 2 CI 2 ) and extracted 3x into EtOAc (lOx the volume of CH 2 CI 2 ).
- the organic layers were dried with Na 2 S0 4 and concentrated to a solid.
- the serine derivative and imidazole (1.2 eq.) were dissolved in CH 2 CI 2 (0.6 M) at r.t. and TBSCI (1.1 eq.) was added in one portion.
- the reaction turned cloudy and would clear over time.
- the reaction was stirred for 6 h and then diluted with EtOAc (20x the volume of CH 2 CI 2 ) before being washed 3x washed with 1 M HCI (20x the volume of CH 2 CI 2 ).
- C NM (126 MHz, CDCI 3 ) ⁇ 151.76, 150.62, 138.38, 122.90, 93.33, 80.30, 76.87, 60.87, 31.84, 29.62, 29.54, 29.41, 29.29, 28.81, 28.22, 22.61, 14.05.
- triphenylmethylphosphonium bromide 2.0 eq.
- THF 0.1 M
- n-BuLi n-BuLi in hexanes
- the reaction was warmed to r.t. for 30 m before cooling back to -78 °C, when the neat aldehyde was added to the reaction dropwise.
- the reaction was then warmed to r.t. and stirred for 12 h.
- the reaction was then diluted with Et 2 0 (8x the volume of THF) and immediately filtered through a pad of silica gel and purified by column chromatography to yield the title compound. 63% over 2 steps. Clear and colorless oil.
- hydrochloride (9) General procedure A was used to convert 9d (126 mg, 0.36 mmol) to the title product.
- the solid was purified via flash chromatography.
- the hydrochloride salt was prepared by the dropwise addition of 2 M HCI in ether to the purified amidine.
- the ether was evaporated, reconstituted in ether, and again evacuated to dryness to yield the title product as tan solid (66% yield).
- R f 0.42 (15% MeOH in CHCI 3 ).
- Procedure B was used to couple 16b (438 mg, 1.43 mmol) and 1-cyano-l-cyclpropanecarboxylic acid (159 mg, 1.43 mmol) to yield the title product as white solid (25% yield).
- R f 0.25 (25% EtOAc in hexanes).
- C NM 75 MHz, CDCI 3 ) ⁇ 170.14, 158.74, 143.24, 141.35, 133.92, 128.78, 127.80, 125.44, 57.87, 35.72, 31.89, 31.37, 29.64, 29.48, 29.33, 29.26, 22.67, 20.60, 14.11.
- methyl 3-dodecylbenzoate (30c) 15.5 mmol of acetyl chloride were added d ropwise over 10 min to 12 mL ice-cold MeOH, and this solution was stirred 5 min. The solid 30b (5.2 mmol) was then added to the solution in one portion. This solution was heated to reflux with stirring for 2 h. At this point solid Na HC0 3 was added to neutralize the solution, which was then filtered through a finely fritted funnel. The solvent was evaporated from the filtrate, and 5.0 mmol of the product were isolated as an am ber oil.
- General procedure B was used to couple 31b (310 mg, 0.93 mmol) and 1-cyano-l- cyclopropanecarboxylic acid (104 mg, 0.93 mmol) to yield the title product as white solid (77% yield).
- R f 0.57 (50% EtOAc in hexanes).
- N-(2-hydroxyethyl)-4-octylbenzamide (33c) Sodium borohydride (0.245 g, 6.47 mmol) was added to 33b (0.395 g, 1.293 mmol) dissolved in TH F (20 m L) and the suspension was stirred at 65 °C for 15 min. Methanol (10 m L, 247 mmol) was added and the reaction went clear over 20 min. The solvent was removed under vacuum and the crude product was dissolved in ethyl acetate, washed with water, brine, and dried over sodium sulfate.
- N-benzyl-4-(4-(oct-l-yn-l-yl)phenyl)cyclohexanamine (34c) General procedure M was used to convert 34b (550 mg, 1.406 mmol) to the title product as a colorless oil (368 mg, 70% yield).
- nonanenitrile (39b) Potassium cyanide (0.829 g, 12.74 mmol) was added to a round bottom flask containing DMSO (5 mL). The mixture was stirred and heated to 60 °C. 1-Bromooctane 39a (2.0 mL, 11.58 mmol) was added dropwise to the flask and the reaction mixture was heated overnight. The reaction was cooled, diluted with water, washed with ether, 6N HCI, water and brine, and dried over sodium sulfate.
- N'-hydroxylnonanimidamide (39c) Hydroxylamine hydrochloride (0.998 g, 14.36 mmol) was dissolved in ethanol (7 mL) in a round bottom flask. 3M NaOH (4.8 mL, 14.36 mmol) was added to the flask. Nonanenitrile 2a (1.00 g, 7.18 mmol) dissolved in ethanol (7 mL) was added to the reaction mixture. The mixture was refluxed at 80 °C for 24 hours. At this time 2a was still visible in the reaction mixture by thin layer chromatography. An additional equivalent of hydroxylamine
- N'-hydroxyltridecanimidamide (40c) Hydroxylamine hydrochloride (213 mg, 3.07 mmol) was dissolved in 95% ethanol (20 mL) in a round bottom flask. 3M NaOH (1.02 mL, 3.07 mmol) and tridecanenitrile 40b (0.30 g, 1.54 mmol) dissolved in 95% ethanol (20 mL) were added to the flask. The reaction mixture was refluxed at 80 °C.
- reaction progress was monitored by TLC and additional equivalents of hydroxylamine and 3M NaOH were added to push the reaction to completion [2 equivalent increments X3 (hydroxylamine hydrochloride (213 mg, 3.07 mmol), 3M NaOH (1.02 mL, 3.07 mmol))].
- X3 hydroxylamine hydrochloride (213 mg, 3.07 mmol), 3M NaOH (1.02 mL, 3.07 mmol)
- heptadecanenitrile (41b) Same procedure as 39b. Product was isolated as a white solid (1.513 g, 92%).
- N'-hydroxylheptadecanimidamide (41c) Hydroxylamine hydrochloride (221 mg, 3.18 mmol) was dissolved in ethanol (10 mL) in a round bottom flask. 3M NaOH (1.06 mL, 3.18 mmol) was added to the flask. Heptadecanenitrile 41b (0.40 g, 1.59 mmol) was dissolved in ethanol (5 mL) and added to the reaction mixture. The reaction was refluxed at 80 °C for 30 hours. TLC analysis indicated that 41b was still present in the reaction mixture.
- C NM 75 MHz, CDCI 3 ⁇ 180.28, 168.78, 163.55, 157.09, 153.41, 146.55, 129.02, 127.64, 124.48, 83.73, 79.83, 36.16, 32.13, 31.45, 30.93, 29.84, 29.70, 29.54, 29.46, 28.41, 28.30, 22.90, 20.55, 14.33.
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AU2014369180B2 (en) * | 2013-12-20 | 2016-11-17 | Novartis Ag | Heteroaryl butanoic acid derivatives as LTA4H inhibitors |
US10100022B2 (en) * | 2014-10-01 | 2018-10-16 | University Of Virginia Patent Foundation | Sphingosine kinase inhibitors |
ES2895850T3 (en) * | 2014-11-24 | 2022-02-22 | Univ Illinois | Procedure for the prevention or treatment of a lung disease or condition |
WO2017129769A1 (en) | 2016-01-28 | 2017-08-03 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Methods for enhancing the potency of the immune checkpoint inhibitors |
US11180489B2 (en) | 2016-03-30 | 2021-11-23 | U niversity of Virginia Patent Foundation | Sphingosine kinase inhibitor amidoxime prodrugs |
EP3756012A1 (en) | 2018-02-21 | 2020-12-30 | INSERM (Institut National de la Santé et de la Recherche Médicale) | Use of sk1 as biomarker for predicting response to immunecheckpoint inhibitors |
US20220089581A1 (en) * | 2019-01-25 | 2022-03-24 | University Of Virginia Patent Foundation | Inhibitors of spinster homolog 2 (spns2) for use in therapy |
CN111362834B (en) * | 2020-02-26 | 2021-04-02 | 湖南大学 | Antibacterial amidine oligomer with drug resistance and preparation method and application thereof |
WO2022056045A1 (en) * | 2020-09-09 | 2022-03-17 | University Of Virginia Patent Foundation | Inhibitors of spinster homolog 2 (spns2) for use in therapy |
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JP2002512954A (en) * | 1998-04-24 | 2002-05-08 | マイトコー | Compounds and methods for treating mitochondrial-related diseases |
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WO2009146112A1 (en) * | 2008-04-02 | 2009-12-03 | University Of Virginia Patent Foundation | Compositions and methods for inhibiting sphingosine kinase |
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